This proposal is a continuation of efforts to understand the biochemical mechanisms that control the cell-type specific activation of the growth hormone gene. A major part of the effort will be focused on the mechanisms that allow GHF-1 to selectively activate the GH and Prl genes in somatotropes and lactotropes. GHF-1 is necessary but not sufficient for activation of either gene. Through use of both conventional and novel screens for protein-protein interactions, the applicant will examine the possibility that selective GH gene activation occurs through interaction of GHF-1 with cell type specific coactivators or adaptor proteins. The involvement of these proteins will be tested by gene targeting experiments. The applicant will use a novel protein-protein interaction detection system to examine potential interactions between GHF-1 and members of the nuclear receptor family. The significance of these interactions will be tested by site directed mutagenesis and transfection experiments. The applicant will examine the genetic mechanisms responsible for activation of the GHF-1 gene during embryonic development and restriction of its expression to progenitors of the somatotrope/lactotrope lineage.